Developmental neurotoxicity testing of chemical mixtures in zebrafish embryos

Developmental neurotoxicity (DNT) is an understudied problem. Every day, people are exposed to complex mixtures of several chemical substances via food intake, inhalation and dermal contact. Nevertheless, risk assessment is performed on single compounds only under the assumption that the individual exposure levels (below no observed adverse effect levels, NOAELs) are predictive of the mixture effect. In the EuroMix project, a method has been developed to evaluate the effects of mixtures of substances, even at or below NOAELs. This method follows the strategy proposed by the European Food Safety Authority (EFSA), and further implements the Adverse Outcome Pathway (AOP) concept as a basis. Currently, assessment of the DNT potential of compounds is performed in costly and time-consuming in vivo rodent studies involving a large number of animals studied over more than one generation. Therefore, from a 3Rs (Replacement, Reduction, Refinement) perspective an alternative approach is needed. The zebrafish (Danio rerio) embryo (ZFE) provides an interesting and potentially useful model to study DNT as neurodevelopment occurs fast with a large resemblance to the higher vertebrate including the human system. Also, from a legal perspective, experimental work with zebrafish embryos within 120 hours post-fertilization, is not considered an animal experiment. Combined with the ease of culture and the high reproduction rate this renders the ZFE a suitable model for high throughput DNT testing in vitro. One of the suitable readouts for DNT testing is neurobehavior since it provides integrated information on the functionality/status of the full nervous system of the embryo. Within 120 hpf the embryo develops from a fertilized egg to a fully functional embryo responsive to environmental stimuli such as light and sound (vibration). The present Ph.D. study investigated the potential human health risk caused by the simultaneous exposure of chemical substances and the need to include the mixtures in the risk assessment. To obtain a real-life picture ofenvironmental pollution by chemical mixtures, an UHPLC-MS/MS-MRM method was developed and validated for screeining pesticide residues on raw and processed tomatoes. Then, the attention was focused on the potential use of the zebrafish model for assessing the chemical mixtures effects in DNT. Recognised that pharmaceuticals display a well-known MOA and are known to cause DNT, their use as model compounds instead of pesticides was preferred. Therefore, the combined effect of three psychoactive pharmaceuticals of concern, Carbamazepine (CBZ), Fluoxetine (FLX), Venlafaxine (VNX) and their main metabolites, Carbamazepine 10,11 -epoxide (CBZ 10,11E), Norfluoxetine (norFLX), and Desvenlafaxine (desVNX), was studied using the zebrafish embryos as a study model. At first, single-compound concentration-effect relationships were assessed as input for dose-response modelling following the benchmark approach leading to a classification of compounds based on potency. Subsequently, a binary mixture was composed based on the relative potency of the individual compounds and tested for their effect on neurological development. To support the assessment of developmental neurotoxicity, the gene expression of three specific DNT markers was investigated

A Counterfactual Safety Margin Perspective on the Scoring of Autonomous Vehicles' Riskiness

Autonomous Vehicles (AVs) have the potential to provide numerous societal benefits, such as decreased road accidents and increased overall transportation efficiency. However, quantifying the risk associated with AVs is challenging due to the lack of historical data and the rapidly evolving technology. This paper presents a data-driven framework for comparing the risk of different AVs' behaviors in various operational design domains (ODDs), based on counterfactual simulations of "misbehaving" road users. We introduce the concept of counterfactual safety margin, which represents the minimum deviation from normal behavior that could lead to a collision. This concept helps to find the most critical scenarios but also to assess the frequency and severity of risk of AVs. We show that the proposed methodology is applicable even when the AV's behavioral policy is unknown -- through worst- and best-case analyses -- making the method useful also to external third-party risk assessors. Our experimental results demonstrate the correlation between the safety margin, the driving policy quality, and the ODD shedding light on the relative risk associated with different AV providers. This work contributes to AV safety assessment and aids in addressing legislative and insurance concerns surrounding this emerging technology

Solar polar orbiter : a solar sail technology reference study

An assessment is presented of a Solar Polar Orbiter mission as a Technology Reference Study. The goal is to focus the development of strategically important technologies of potential relevance to future science missions. The technology is solar sailing, and so the use of solar sail propulsion is, thus, defined a priori. The primary mission architecture utilizes maximum Soyuz Fregat 2-1b launch energy, deploying the sail shortly after Fregat separation. The 153 × 153 m square sail then spirals into a circular 0.48-astronomical-unit orbit, where the orbit inclination is raised to 90 deg with respect to the solar equator in just over 5 years. Both the solar sail and spacecraft technology requirements have been addressed. The sail requires advanced boom and new thin-film technology. The spacecraft requirements were found to be minimal because the spacecraft environment is relatively benign in comparison with other currently envisaged missions, such as the Solar Orbiter mission and BepiColombo

The Gaia mission

Gaia is a cornerstone mission in the science programme of the EuropeanSpace Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach. Both the spacecraft and the payload were built by European industry. The involvement of the scientific community focusses on data processing for which the international Gaia Data Processing and Analysis Consortium (DPAC) was selected in 2007. Gaia was launched on 19 December 2013 and arrived at its operating point, the second Lagrange point of the Sun-Earth-Moon system, a few weeks later. The commissioning of the spacecraft and payload was completed on 19 July 2014. The nominal five-year mission started with four weeks of special, ecliptic-pole scanning and subsequently transferred into full-sky scanning mode. We recall the scientific goals of Gaia and give a description of the as-built spacecraft that is currently (mid-2016) being operated to achieve these goals. We pay special attention to the payload module, the performance of which is closely related to the scientific performance of the mission. We provide a summary of the commissioning activities and findings, followed by a description of the routine operational mode. We summarise scientific performance estimates on the basis of in-orbit operations. Several intermediate Gaia data releases are planned and the data can be retrieved from the Gaia Archive, which is available through the Gaia home page. http://www.cosmos.esa.int/gai

Simultaneous determination and dietary risk assessment of clethodim and its metabolites in different fruits and vegetables

Clethodim is one of the most widely used herbicides in agriculture and, after field application, is metabolised to several metabolites. The potential toxicological negative effects of these compounds are poorly understood. Thus, recently, within the risk assessment framework, the European Food Safety Authority (EFSA) proposed to include the minor metabolites in the definition of clethodim residue. In this work, an easy to use and reliable UHPLC method coupled with a triple quadrupole MS/MS was developed and validated for the detection and quantification of the herbicide clethodim and related metabolites clethodim sulphone, clethodim sulphoxide, metabolites M17R and M18R in apple, grape, olive and rice. The five analytes were extracted by using a modified QuEChERS procedure, while the active ingredients were determined in multiple reaction monitoring (MRM) ion-switching mode. The proposed method showed calibration curve linearity with r2≥0.990 for all active ingredients (a.is.) both in solvent and matrix extracts. Limits of quantitation (LOQ) of the five compounds ranged from 9.44g/kg for M17R in olive extract to 11.01g/kg for clethodim in apple extract. Recoveries values ranged from 86% to 119% at two concentration levels (LOQ and 10xLOQ), while the intraday and interday precisions of the method were both below 10% in all cases. The method was successfully used for the quantification of the five a.is. in different food matrices. Furthermore, chronic dietary risk was investigated using a hazard quotients (HQ) method based on European dietary habits. The chronic dietary exposure risk quotients ranged from 1.0*10-5 (lower bound scenario) to 2.7*10-4 (upper bound scenario) which were significantly lower than 1. Data obtained indicate that the dietary exposure risks were acceptable for clethodim and its major and minor metabolites applied in apple, table grape, rice and table olive

GeoSail: an elegant solar sail demonstration mission

In this paper a solar sail magnetotail mission concept was examined. The 43-m square solar sail is used to provide the required propulsion for continuous sun-synchronous apse-line precession. The main driver in this mission was found to be the reduction of launch mass and mission cost while enabling a nominal duration of 2 years within the framework of a demonstration mission. It was found that the mission concept provided an excellent solar sail technology demonstration option. The baseline science objectives and engineering goals were addressed, and mission analysis for solar sail, electric, and chemical propulsion performed. Detailed subsystems were defined for each propulsion system and it was found that the optimum propulsion system is solar sailing. A detailed tradeoff as to the effect of spacecraft and sail technology levels, and requirements, on sail size is presented for the first time. The effect of, for example, data acquisition rate and RF output power on sail size is presented, in which it is found that neither have a significant effect. The key sail technology requirements have been identified through a parametric analysis

Terrestrial planet sample return missions using solar sail propulsion

An assessment of terrestrial planet sample return missions utilising solar sail propulsion is presented, in addition to sample return from a high inclination near-Earth asteroid, 2001 QP153. Payloads have been sized based on existing studies or have been custom designed and sized. Heliocentric and planetocentric trajectory analysis has been conducted to assess the sail performance level required to return samples within a reasonable timescale, whilst maintaining manageable sail dimensions. Sail technology is based on projected data from existing development programmes. Solar sailing appears to offer modest benefits in returning a sample from Mars or Venus, but significant benefits for Mercury Sample Return. In addition, sample return from high-energy targets such as asteroid 2001 QP153 appears to be only possible when using the solar sail as the enabling propulsion technology

Determination of Pesticide Residues in IV Range Artichoke (<i>Cynara cardunculus</i> L.) and Its Industrial Wastes

Fourth-range products are those types of fresh fruit and vegetables that are ready for raw consumption or after cooking, and belong to organic or integrated cultivations. These products are subject to mild post-harvesting processing procedures (selection, sorting, husking, cutting, and washing), and are afterwards packaged in packets or closed food plates, with an average shelf life of 5–10 days. Artichokes are stripped of the leaves, stems and outer bracts, and the remaining heads are washed with acidifying solutions. The A LC-MS/MS analytical method was developed and validated following SANTE guidelines for the detection of 220 pesticides. This work evaluated the distribution of pesticide residues among the fraction of artichokes obtained during the industrial processing, and the residues of their wastes left on the field were also investigated. The results showed quantifiable residues of one herbicide (pendimethalin) and four fungicides (azoxystrobin, propyzamide, tebuconazole, and pyraclostrobin). Pendimethalin was found in all samples, with the higher values in leaves 0.046 ± 8.2 mg/kg and in field waste 0.30 ± 6.7 mg/kg. Azoxystrobin was the most concentrated in the outer bracts (0.18 ± 2.9 mg/kg). The outer bracts showed the highest number of residues. The industrial waste showed a significant decrease in the number of residues and their concentration

Occurrence of acrylamide, hydroxymethylfurfural and furaldehyde as process contaminants in traditional breakfast cereals: “Bsissa”

Hydroxymethylfurfural (HMF), furaldehyde (FAL) and acrylamide (AA) are produced during the food roasting process. The content of these toxic products in a common ready-to-eat breakfast, known as “Bsissa”, was investigated. This North African traditional food is mainly based on roasted cereals, leguminous and spices. In the present study, thirty-four commercial “Bsissa” have been investigated for their toxic HMF, FAL and AA content using RP-HPLC-DAD. Additionally, to distinguish the main way of the production of these toxic products (Maillard reaction or caramelization origin), total protein, carbohydrates and reducing sugar were quantified and found in the range 5.63–25.72 g, 45.75–84.33 g and 0.37–3.74 g per 100 g of Bsissa, respectively. This result makes it also suitable to cover daily needs as a breakfast food. Obtained results showed that HMF and FAL were detected in most samples, with values not exceeding 24.71 mg/100 g and to 3.91 mg/100 g, respectively. AA was not detected in all the studied samples. Principal components (PC) and hierarchical classification were employed to establish the samples’ heat damage based on relations between variables. Two PCs were obtained which explain more than 75% of the total variance, thus grouping the Bsissa in two clusters based on the main used cereal. This analysis may help in the mitigation step of furanic compounds by choosing the appropriate Bsissa ingredients